This project is based on our discovery that antigens, the substances that trigger an immune response, can induce the programmed death, or apoptosis, of activated, specifically-reactive T lymphocytes. Our work has shown that this mechanism is built-in to T cells to preserve immune homeostasis and tolerance by preventing the overexpansion of antigenically-stimulated T cells. We are studying this process at the cellular and molecular level to better understand the regulation of T lymphocytes in healthy and diseased immune systems. We have focused on determining what stimuli lead to T cell death and how signals for death are processed inside the cell. In the past year we have developed new information about how death cytokines (CD95 ligand and tumor necrosis factor) control T cell apoptosis. These advances provide fundamental insights into how immune responses are regulated in mammals. They may also shed light on diseases such as AIDS in which T cells undergo apoptosis on how to better develop vaccines to enhance immune responses, and on how to design immunomodulatory drugs to treat immunological diseases.